Patent GB-815629-A (GB)
Title: New derivatives of benzimidazole and its salts and process for the manufacture of these derivatives
Inventor: HERRLING SIEGFRIED
IPC: C07D235/08
Filed: 1956-10-15
Abstract: This invention comprises benzimidazoles of the general formula <FORM:0815629/IV (b)/1> and salts of these compounds with acids, in particular salts with the penicillins, in which X is an alkyl radical (1-4 carbon atoms) and if desired substituted by hydroxyl groups, Y is a halogen atom and R1 to R4 are the same or different and are hydrogen atoms, lower alkyl groups (1-3 carbon atoms), halogen atoms or nitro groups and a process for the preparation thereof wherein (a) an o-phenylene diamine, substituted in one of the amino groups by a p-halogeno-benzyl radical, and in the benzene ring by R1 to R4 is reacted with a compound RX where R is a group capable of reacting with an o-phenylene diamine to form a benzimidazole, (b) a Schiff's base of the formula <FORM:0815629/IV (b)/2> is oxidized to the benzimidazole, (c) a benzimidazole unsubstituted in the 1 position but otherwise substituted as represented above or a metal derivative thereof is reacted with a halogenobenzyl halide, or (d) an N-(p-halogeno benzyl)-o-nitroaniline, substituted in the benzene nucleus by R1 to R4 is acylated with a compound R1-X wherein R1 is a group capable of converting an amine into an acylation product thereof, the imidazole ring being closed after reduction of the nitro group; also pharmaceutical preparations containing the products (see Group VI).  In exaples, 2-methyl benzimidazole is reacted with sodamide and p-chlorobenzyl bromide in dioxane or toluene or with potassium hydroxide and p-chlorobenzyl bromide in dimethylformamide, to form 1-p-chlorobenzyl-2-methylbenzimidazole.  Similarly are prepared 1-p-chloro - benzyl - 2 - ethyl- and -2 - propyl-benzimidazoles, 1 - p - chlorobenzyl - 2 - (iso - butyl)-benzimidazole hydrochloride, 1 - p - chlorobenzyl - 2 - methyl - 5,6 - dinitro- and -5,6-dichloro benzimidazoles from the appropriately substituted benzimidazoles.  In other examples p-chlorobenzyl-o-phenylenediamine is reacted with glacial acetic acid or glycollic acid to yield 1 - p - chlorobenzyl - 2 - methyl- or -2 - hydroxymethyl - benzimidazole; N - acetyl - N - (p - chlorobenzyl)-o-nitroaniline is reduced by iron powder and acetic acid to form 1-p-chlorobenzyl-2 - methylbenzimidazole; and N - (p - chloro - benzyl) - o - phenylenediamine hydrochloride is reacted with butyraldehyde and copper acetate to form 1 - p - chlorobenzyl - 2 - propylbenz - imidazole.  Examples of the preparation of the penicillin-G salts are given wherein penicillin-G-triethanolamine salt dissolved in water or methanol:water (1:1) and 1-p-chlorobenzyl-2-methylbenzimidazole in the same solvent is mixed and the penicillin salt of the benzimidazole separates. Alternatively, the pencillin-G is used in the form of the free acid and chloroform, ether and butyl acetate used as solvents.  The penicillin-G salt of 1-p-chlorobenzyl-2-hydroxymethylbenzimidazole is also prepared. Specifications 703,272 and 703,273 are referred to.ALSO:The invention includes solutions, suspensions, ointments, pastes, gels, powders, tablets, and capsules which contain a benzimidazole derivative of the general formula <FORM:0815629/VI/1> in which X is an alkyl radical (1-4 carbon atoms) and if desired substituted by hydroxy groups, Y is a halogen atom and R1 to R4 are the same or different and are hydrogen atoms, alkyl radicals, halogen atoms or nitro groups, or salts of these derivatives with acids, including the penicillins, together with an inert pharmaceutical carrier.  Specifications 703,272 and 703,273, [both in Group IV (b)], are referred to.